Asthma and other respiratory diseases have long been treated by the inhalation of appropriate medicament. For many years a widely used and convenient choice of treatment has been the inhalation of medicament from an aerosol created by a pressurized metered dose inhaler (pMDI). Formulations used in pMDIs often comprise particles of medicament suspended in liquefied propellant(s), e.g. CFC propellant(s) and more recently non-CFC propellant(s), such as 1,1,1,2-tetrafluoroethane (HFA134a) and/or 1,1,1,2,3,3,3-heptafluoropropane (HFA227).
The consistency/uniformity of the metered dose delivered from a suspension-based pMDI may be compromised in a number of ways. In particular there is generally a difference between the specific gravity of the solid medicament to be dispensed and the liquid component of the aerosol formulation (for example propellant or propellant mixture or mixture of propellant(s) and, if used, liquid excipient(s)). This means that with time, the two components (solid and liquid) tend to separate within the formulation chamber of the container with the more dense component(s) settling to the bottom (sedimenting) and the less dense component(s) rising to the top (creaming). In a number of medicinal aerosols, the medicament has a higher specific gravity (density) than that of the liquid component of the formulation (e.g. propellant(s)). This often holds true for formulations based on HFA134a. In such formulations the particles of medicament tend to sediment to the bottom of the aerosol container, and for pMDI devices in which the metered dose valve is oriented at the bottom of the container, the medicament sediments within the formulation chamber of the container onto and around the valve. In other formulations, where the medicament has a lower specific gravity than that of the liquid component of the formulation, the medicament particles tend to cream to the top liquid/vapor interface within the formulation chamber of the container, and thus move away from the metered dose valve in pMDI devices with the metering valve oriented at the bottom of the aerosol container. The tendency of particles of a particular medicament to sediment or cream, as the case may be, may be accentuated by flocculation of the suspended medicament particles, whereby the flocculation of a suspension can increase the effective particle size from 10 microns or less to well over 1 mm due to the formation of large flocs. This holds particularly true when using HFA 134a and/or HFA 227, because suspensions of many drugs in formulations containing these propellants generally flocculate more coarsely than in formulations with CFC propellants. Although users of suspension aerosols are always instructed to shake (or agitate) the container well immediately prior to use, even a short delay between shaking and actuation of the device may be sufficient to allow some sedimentation or creaming (as the case may be) to occur, resulting in the device dispensing, and the user receiving, a dose containing an elevated or a reduced amount of the medicament, respectively.
GB 2,195,986 describes an aerosol metering valve wherein the pick-up point, i.e. the point at which substance passes from the interior of the container into the valve, is at a location which, when the container is oriented with the valve at the bottom, is spaced an appreciable vertical distance from the nearest substantially horizontal surface, thus ensuring that material entering the metering chamber comes from above the nearest region where any sedimented drug particles might gather. By deliberately placing the pick-up point appreciably higher than the lowest point in the container, a significant quantity of the contents of the container cannot be dispensed, resulting in considerable wastage. U.S. Pat. No. 6,170,717 discloses an aerosol metering valve comprising a valve body having at least one orifice to allow a quantity of suspension of substance in liquid propellant to pass from the container into the valve wherein the valve further comprises a ring provided with a trough and the ring is disposed around the valve body below the orifice to reduce the volume of suspension that can be accommodated within the container below the orifice when the container is oriented with the valve at the bottom, thereby ensuring that most of the contents of the container may be dispensed and to allow for accommodation of any drug particle sediment within the trough of the ring thus ensuring that the suspension entering a chamber of the valve comes from above the region where any sedimented particles might gather.